The primary goal of this project is to identify clinical targets that predict eye-specific optic nerve head (ONH) behavior (depth of cupping) and retinal ganglion cell (RGC) axon susceptibility within the monkey unilateral experimental glaucoma model so as to translate this knowledge to human patients in future research. We test three hypotheses regarding the relationships between eye-specific behavior, ONH connective tissue remodeling and RGC axon susceptibility. First, that stiff eyes are more susceptible to a shallow form of cupping and RGC axon loss than compliant eyes at similar levels of IOP insult. Second, that the behavior and susceptibility of individual eyes can be predicted from the results of in viv spectral domain optical coherence tomography (SDOCT) ONH compliance testing, post-mortem 3D reconstruction of the ONH connective tissues and stress/strain outputs of engineering finite element (FE) models. Third, that ONH connective tissue remodeling contributes not only to the depth of cupping but to RGC axon susceptibility by being both more robust and more protective of axons in compliant and/or young ONHs. Aim 1 is to characterize age-related differences in ONH behavior and susceptibility among young, adult and old monkey eyes followed from early to severe experimental glaucoma. Aim 2 is to identify those components of normal SDOCT ONH compliance testing and post mortem ONH 3D reconstructions and FE models that best predict eye-specific differences in ONH behavior/susceptibility. Aim 3 is to test predictions regarding the fundamental anatomical nature of ONH connective tissue remodeling and its relationships with RGC axon susceptibility and age in early monkey experimental glaucoma. The methodology includes: longitudinal 870 and 1050 nm SDOCT ONH dataset acquisition; their visualization, delineation and quantification within custom Multiview software; 3D episcopic fluorescent ONH reconstruction; automated 100% optic nerve axon counts; and characterization of the relationships between ONH connective tissue remodeling, axonal myelination and astrocyte phagocytosis by immunohistochemistry, in situ hybridization and, serial block-face scanning electron microscopy. Expected outcomes include: identification of clinical targets that predict the regional pattern and magnitude of eye connective tissue deformation and axon loss in glaucoma; improved clinical imaging tools necessary for predicting human eye-specific IOP and ONH progression targets; support for the conclusion that laminar remodeling is a deformation-driven phenomenon and therefore occurs in the most compliant eyes and/or in those eyes with the highest IOP at all ages; and support for the conclusion that where remodeling occurs, the mechanisms of axonal insult and/or preservation include age-related differences in astrocyte and microglial remodeling and phagocytosis of newly engulfed myelin. These findings will set the stage for studying effective neuroprotective interventions in future proposals.